Treatment of human diseases involving dysregulation or dysfunction of the nervous system

ABSTRACT

A method of preventing, treating and/or controlling diseases caused by dysregulation and/or dysfunction of various portions of the nervous system which comprises administering to a patient, an effective amount of a compound of the avermectin family, e.g. ivermectin, in single or multiple doses of up to 1.6 mg/kg at intervals of from 3 days to 4 months.

This is a divisional of application Ser. No. 07/711,759, filed Jun. 7,1991 now U.S. Pat. No. 5,189,026.

BACKGROUND

1. Field of Invention

This invention relates to the use of the C-076 family of compounds, i.e.avermectins, for the prevention, treatment and control of variousdiseases in humans caused by dysregulation and/or dysfunction of variousportions of the human nervous system. More particularly, this inventionrelates to the administration of the avermectin class of compounds (1)to prevent, treat, and control such diseases in humans as seizures,dystonic movements, tremors, degenerative conditions of the brain,spinal cord, and peripheral nerves, spasticity of both brain and spinalcord origin, and various types of psychoses and personality disorders,(2) to increase tonic activity of the parasympathetic nervous system, asin bladder and bowel control, (3) to decrease activity of thesympathetic nervous system at cutaneous and cardiovascular levels, (4)to ameliorate depression, (5) to regularize the sleep-wake cycle, (6) todecrease addictive and abusive behavior, (7) to increase attention spanand improve behavior of mentally-deficient children and adults, (8) totreat autoimmune disorders, (9) to treat malignant states, and (10) toprevent or ameliorate anoxic or ischemic damage to the nervous system,as well as specific pharmaceutical formulations and treatment regimensfor such prevention, treatment and control. The preferred compound whichis used to illustrate this invention is ivermectin. Ivermectin is asemi-synthetic derivative of avermectin and is generally produced as amixture of at least 80% 22,23-dihydroavermectin B_(1a) and less than 20%22,23-dihydroavermectin B_(1b). The following structural formularepresents the avermectin series of compounds, which compounds can bechemically converted to useful derivatives as discussed below. ##STR1##wherein R is the 4'-(alpha-L-oleandrosyl)-alpha-L-oleandrose group ofthe structure: ##STR2## and wherein the broken line indicates a singleor double bond; R₁ in hydroxy and in present only when said broken lineindicates a double bond; R₂ in isopropyl or sec-butyl; and R₃ in methoxyor hydroxy.

2. Prior Art

The avermectin family, of which ivermectin, a chemically producedanalog, is a member, is a series of compounds isolated from thefermentation broth of a C-076 producing strain of Streptomycesavermitillis and also chemically produced derivatives thereof. At leasteight distinct but closely related compounds are produced by S.avermitillis, A_(1a), A_(1b), A_(2a), A_(2b), B_(1a), B_(1b), B_(2a),and B_(2b). Their production is described in U.S. Pat. No. 4,310,519.The preparation of is disclosed in U.S. Pat. No. 4,199,569. Thedisclosures of each of the foregoing patents are incorporated herein byreference. The avermectin family of compounds is a series of potentantiparasitic agents known to be useful against a spectrum ofendoparasites and ectoparasites in mammals arid to have agriculturaluses against various nematode and insect parasites found in and on cropsand in soil.

Some of the avermectins contain a 22,23-double bond. This may beselectively reduced to prepare the ivermectin compounds. In addition,the avermectins possess a disaccharide moiety at the 13-positionconsisting of the alpha-L-oleandrosyl-alpha-L-oleandrosyl group. One orboth of these saccharide groups may be removed as described in U.S. Pat.No. 4,206,205. The thus produced aglycone derivatives have a hydroxygroup at the 13-position. This group may be removed to form the 13-deoxycompound as described in U.S. Pat. Nos. 4,171,314 and 4,173,571; thelatter patent also describes the 13-halo derivatives. The avermectincompounds and derivatives have several hydroxy groups which may beacylated as described in U.S. Pat. No. 4,201,861. derivatives ofavermectin and ivermectin are disclosed in U.S. Pat. Nos. 4,333,925 and4,963,667. All the aforementioned patents are incorporated herein byreference. The compounds disclosed in the patents mentioned above sharethe property of antiparasitic activity with ivermectin.

Since all the compounds mentioned and referred to above share thespectrum of anti-parasitic biological activity of ivermectin, varyingonly in degree, it is expected they will share the activity spectrumneeded to make them suitable for use in this invention. In order toestablish their potency and selectivity as compared to ivermectin, othermembers of the avermectin class could be screened utilizing in vitro andin vivo models already known from the literature. Compounds which lookpromising for preventing, treating or controlling a particularindication in the in vitro screens are tested further in animal models.Those with the potency desired in the animal models are then furtherselected for testing in human pharmacodynamic models and clinicaltrials.

In vitro screens which are suitable include (1) the binding of the testcompounds as radio labeled derivatives thereof to preparations ofgamma-aminobutyric acid (GABA) receptors, subtypes A and B, (2) thedisplacement of the binding of other known GABA A and B receptoragonists by the avermectin compounds, (3) examination of the ability ofeither the avermectin compounds, or of other GABA agonists plus theavermectin compounds, to bind in the presence of GABA, and (4) effectsof the avermectin compounds on the release and uptake of GABA by brainor nerve preparations. The tests described herein are disclosed in thefollowing publications: Sigel, et al. Mol. Pharmacol., 32, 749-52(1987); Soderlund, et al., Biochem, Biophys. Res. Comm. 146, 692-698(1987); Kirkness, et al., Eur. J. Pharmacol., 150, 385-388 (1988) ;Robertson, Br. J. Pharmacol., 98, 167-176 (1989); Chu, et al., Neurol.,37 , 1454-1459 (1987); Bhisitkul, et al., Exp. Brain Res., 66, 659-663 (1987); Kerr, et al., Brain Res., 405, 150-154 (1987); Price, et al.,Nature, 307, 71-74 (1984); Bowery, et al., Neuropharmacol., 23, 219-231(1984); Olsen, et al., FASEB J., 4, 1469-1480 (1990); and Erickson, Sci.Amer., 264, (5) 124 (1991). All four types of assays can be performedusing GABA preparations derived from different regions of the brain,spinal cord, peripheral nerves, and various body organs.

In vivo screens suitable for testing include using animal models forseizures and for spasticity. Suitable seizure models are disclosed inPorter, et al., Cleveland Clin. Quart.,51, 293-305 (Summer 1984);McNamara, et al., Neuropharmacol., 27, 563-568 (1988) ; and McNamara,Epilepsia, 30, suppl 513-518 (1989). Suitable spasticity models aredisclosed in Coward, Triangle, 20, 151-158 (1981); Davies, Br. J.Pharmacol., 76, 473-481 (1982); Davies, et al., Br. J. Pharmacol., 78,137-142., (1983), and Sayers, et al., Arzneimittel-Forschung, 30,793-803 (1980).

Comparative human pharmacodynamic studies are then conducted using thecompounds with the particular biological profile predicted from the invitro and animal screens. The human tests which are suitable aredisclosed in Hagbarth, J. Neurol. Neurosurg. Psychia., 23, 222-227(1960); Hagbarth, et al., J. Neurol. Neurosurg. Psychia., 31, 207-213(1968); Hassan, et al., J. Neurol. Neurosurg. Psychia., 43, 1132-1136(1980); Knutsson, et al., Scand. J. Rehabil. Med., 12, 93-106 (1980);Knutsson, Triangle, 21, 13-20 (1982); Knutsson et al. J. Neurol. Sci.,53, 187-204 (1982); and Kugelbert, Electroenceph. Clin Neurophysiol.,Suppl. 22, 103-111 (1962).

The only use for human patients described in the literature for theavermectins, and ivermectin in particular, is for treating nematodeparasites, particularly onchocerciasis (river blindness) utilizingdosages of up to 150 micrograms per kilogram of body weight. No sideeffects of significance were reported and no teratogenic activity wasfound, Pacque, et al., Lancet, 335, 1377-1380 (1990) and Pacque, et al.,Lancet, 336, 1486-1489 (1990).

Many members of the avermectin class, in particular ivermectin, arepotent and highly selective parasiticides which are lethal forinvertebrates from a variety of phyla, ranging from insects to nematodeworms. Much work has been done to determine the mechanism of action andthe safety for use in mammals. Many investigators conclude thativermectin and avermectin B achieve their results in invertebrates byindirectly potentiating or mimicking the action of the neurotransmitterGABA. See Campbell, et al., Science, 221, 823-828, (1983); Campbell, etal., J. Vet. Pharmacol. Therap., 7, 1-16, (1984); Terada, et al.,Exp.Parasitol., 57, 149-157, (1984); Bennett, JAVMA, 189, 100-104, (1986);Chalmers, et al., Eur. J. Pharmacol. 129, 371-374, (1986). Someinvestigators find other explanations and cast doubt on the accuracy ofthe GABA agonist theory. See Martin, et al., Br. J. Pharmacol.98,747-756, (1989). The parasites are believed to be killed as aconsequence of centrally- or peripherally-mediated muscular paralysis.Tn the families of invertebrates affected, excessive GABA-ergic activityinhibits the process of neuromuscular transmission, see Bennett, supra.

Studies and experiments, attempting to determine if ivermectin exhibitsGABA agonistic properties, have shown that ivermectin exhibits suchproperties in mammalian nervous tissues in vitro, at concentrationsranging from 10⁻⁷ M to 10⁻⁵ M, with levels of 10⁻⁶ M or higher generallybeing required to produce a 50% change in the parameters studied, Sigel,et al., (1987) supra; Soderlund, et al., (1987) supra; Kirkness, et al.,(1988) supra; and Robertson, (1989) supra.

It was found by investigators that intravenous administration of 0.3mg/kg in rats resulted in very small amounts of ivermectin entering thecentral nervous system. See Campbell, et al., (1983) supra; Campbell etal., (1984) supra, and Bennett, (1986) supra. Utilizing high doses indogs and swine resulted in signs suggestive of activity at the level ofthe central nervous system. See Campbell et al., (1984) supra. However,in the investigations in vitro, the activity of ivermectin does notconclusively demonstrate that it acts as a GABA agonist. The resultsindicate it has a relatively slow onset of action, loses its activitywithin minutes of administration, and at times acts as a blocker ratherthan an activator of GABA-sensitive chloride channels, Sigel, et al.,(1987) supra; and Robertson, (1989) supra; In mouse brain preparations,ivermectin may actually inhibit the channel-opening actions of GABA asnoted by Soderlund, et al., ( 1987) supra. In guinea pig brainpreparations, investigators found that many actions of ivermectinresemble those of the GABA antagonist picotoxin, Kirkness, et al.,Turner (1988) supra.

In investigations to determine the effects of doses large enough toaffect the central nervous system of mammals, the clinical signsproduced indicated that the central nervous system was profoundlydepressed, as evidenced by listlessness and ataxia, followed by loss ofupright posture and death, Campbell et al., (1984) supra and Soderlundet al., (1987) supra, citing the unpublished paper of Bloomquist, et al.

There is nothing in the aforesaid publications which shows, speculatesor predicts the effects of avermectins in general or ivermectinspecifically on humans, i.e. on cardiovascular, gastrointestinal,parasympathetic or sympathetic systems, immune systems, on diseasestates or dysregulations of the nervous system, or on personality, mood,behavior, memory, attention span or cognitive status. Other GABAagonists known to be active in humans, such as the benzodiazepinetranquilizers, baclofen muscle relaxants and anti-convulsants such asvalproic acid and gabapentin, are active to some extent in treatinganxiety, as minor anesthesia agents, in treating spasticity, and forseizure control. They also have strong potential to cause cognitivechanges, lethargy, somnolence, depression, psychotic behavior,respiratory depression, coma and death, particularly when taken inoverdoses or for long periods of time. There is therefore a need for anactive agent with GABA agonist properties that possesses all thebeneficial effects of the putative GABA agonists, without the potentialfor toxicity of the other known members of this pharmacological class.

SUMMARY OF INVENTION

We have discovered that, surprisingly, the avermectins, whenadministered to humans in single or multiple doses of up to 1.6 mg/kg ofbody weight, have the pharmaceutical activities in humans which aregenerally considered to be due to GABA agonist properties, as well asother activities which may or may not be traceable to GABA agonistproperties in humans, and yet are very safe with little or no adverseside effects.

The preferred avermectin for use in this invention is ivermectin, whichdisplays superior effects compared to other so-called GABA agonists whenadministered in effective amounts as an agent to treat diseases causedby dysregulation or dysfunction of various portions of the nervoussystem. Thus, this invention is a method for prevention, treatment andcontrol of disease states in humans caused by nervous systemdysregulation and dysfunction, which comprises administering to apatient in need of such treatment an effective amount of an avermectincompound. The amount of the avermectin compound administered to beeffective is preferably from 0.1 to 1.6 mg/kg of body weight, atintervals of from 3 days to 4 months. The methods of administration arepreferably rectal or subcutaneous. The ivermectin compound preferred foruse in this invention is Ivermectin. The methods of prevention,treatment and control for which the active compounds are effectiveaccording to this invention are seizure control, diminution of dystonicmovements and tremors, significantly decreasing spasticity of both brainand spinal cord origin, e.g. closed head injuries, cerebral palsy,strokes, and spinal cord injuries. In addition, the compounds areeffective to increase tonic activity of the parasympathetic nervoussystem in the bladder and the bowel, to decrease activity of thesympathetic nervous system at cutaneous and cardiovascular levels, toameliorate depression, to improve mood, to regularize the sleep-wakecycle, to decrease addictive behavior, and to markedly increase theattention span and to improve the behavior of mentally deficientchildren and adults.

The avermectins are also effective in the re-establishment of normal andappropriate body homeostatic mechanisms. Thus, the compounds are alsoactive in the treatment or palliation of malignancies, or in thealteration of the sensitivity of malignant cells to exogenouschemotherapeutic agents. For the former reason, i.e. re-establishment ofnormal and appropriate body homeostatic mechanisms, the avermectins arealso active in the treatment of rheumatoid arthritis, osteoarthritis,systemic lupus erythematosus, spondylarthropathies, Crohn's disease,ulcerative colitis and connective tissue disorders in general.

DETAILED DESCRIPTION

This invention is based on the discovery that avermectin compounds,including synthetic derivatives thereof, surprisingly have propertieswhich enable them to be used to treat a large number of disease statesin humans which are caused, directly or indirectly, by dysregulationand/or dysfunction of various portions of the nervous system.

This invention provides a method of administering an avermectincompound, preferably ivermectin, to patients in need of suchadministering for preventing, treating and controlling (1) seizuredisorders, i.e. epilepsy, (2) diseases associated with damage to ordysfunction of the extrapyramidal system resulting in dystonia and/ortremors, e.g. movement disorders such as Huntington's chorea, familialtremors, muscular dystonia and spastic retrocollis, and congenitaldegeneration of the basal ganglia, (3) diseases associated withdegenerative states such as multi-infarct dementia or Binswanger'sdementia, amyotrophic lateral sclerosis, myotonic dystrophy, congenital(hereditary) muscular dystrophies, e.g. Duchenne's and Becker's, motorneuron diseases, spinal muscular atrophy, and Parkinson's disease, (4)diseases caused by acquired lesions of the central nervous systemassociated with spasticity, e.g. closed head injury, multiple sclerosis,cerebrovascular accidents, cerebral palsy, and meningoencephalitis, (5)spinal cord injury and concomitant spasticity, (6) diseases associatedwith dopaminergic dysregulation, e.g. schizophrenia and otherneuropsychiatric disorders in which excessive dopaminergic activity mayplay a role, such as manic depressive illness, major affectivedisorders, behavior disorders and borderline personality states, (7)diseases associated with cortical or subcortical dysregulation of GABA,glutamate, or dopamine, e.g. lesions of peripheral nerves, depression,snoring, sleep apnea, dysregulation of the sleep-wake cycle, seizuredisorders, comatose states, causalgia, reflex sympathetic dystrophy,acute or chronic pain associated with the peripheral nervous system,habituation to or dependency on addictive substances, and acute ischemicepisodes of varying etiologies such as traumatic closed head injury,subarachnoid hemorrhage, anoxic encephalopathy, infectious or metabolicencephalopathy, and hemorrhagic or embolic/atherscleroticcerebrovascular accidents, (8) dysregulation of the sympathetic andparasympathetic nervous systems, e.g. constipation, hypertension,congestive heart failure, reflex sympathetic dystrophy, causalgia,autonomic hyperreflexia, diabetic neuropathy, renal failure and asthma,(9) cardiovascular disorders caused by excessive activity of thesympathetic nervous system such as angina, hypertension,atherosclerosis, congestive heart failure, and arrhythmias, (10)disorders of behavior, personality, affect, and cognition, e.g. patientsin need of cognitive/learning/memory enhancement, depressive states,addictive behavior, mental retardation, sociopathic and psychopathicpersonality disorders, (11) malignant states, e.g. indirectly byaltering the activity of the nervous system or directly by changing thesensitivity of malignant cells to exogenous chemotherapeutic agents and(12) autoimmune disorders in which the nervous system plays a role, suchas rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus,spondyloarthropathies, Crohn's disease, ulcerative colitis and generalconnective-tissue disorders.

The preferred avermectin compound is ivermectin; however, others of theavermectin family of compounds have the same spectrum of activity, eventhough all the compounds are not equally potent. For example,ivermectin, when administered at dosages from 0.1 to 1.6 mg/kg atintervals of from 3 days to 4 months, causes no significant sideeffects. Depending on the disease treated, its effects after single-doseadministration may last from about three days to about three months. Thedosage regimen and strength are determined by the attending clinician'sjudgment, based on the condition and age of the patient and on theseverity and etiology of the disease, as well as on the response totreatment.

The method of administration is preferably rectal, however,subcutaneous, transcutaneous (transdermal), oral, intravenous,intramuscular or intrathecal routes can be used. The dosage forms can bemade by conventional means using generally-recognized-as-safe (GRAS)additives, solvents and excipients, taking into account the highlylipophilic nature of the avermectin compounds. Thus the preferred rectaldosage form comprises the active compound dissolved in a suitablesolvent such as propylene glycol plus glycerol formal. This sameformulation used for subcutaneous injections. It is the same formulationused for veterinary purposes under the trademark IVOMEC. The oral dosagecan be capsules, tablets, dragees, syrups, and the like. The capsules,tablets and dragees, and other solid oral dosage forms, comprise theactive ingredient admixed with a pharmaceutically acceptable carriervehicle such as starch, talc, magnesium stearate, or dicalciumphosphate. The transdermal dosage form can be a conventional patchgenerally used to deliver lipophilic drugs.

In using the active compounds of the avermectin family, mixtures of thecompounds may be used; this is particularly true when using fermentationproducts of the C-076 producing a microorganisms because the isolatedcomponents usually contain a major amount of one component and anotheramount of a minor component. It is not practical to separate thecomponents, and the biological activity of the major component isnegligibly affected. Also, when the fermentation products comprising thetwo components are derivatized chemically, the components are notseparated in either the starting materials or the final product. Thus,the preferred ivermectin compound is normally used as the mixture of atleast 80% 22, 23-dihydroavermectin B_(1a) and at most 20% 22,23-dihydroavermectin B_(1b).

The following examples which illustrate the invention are not intendedto limit the invention.

EXAMPLE 1 Ivermectin Injectable Solution

A sterile solution suitable for rectal or subcutaneous administration isprepared using the following formulation to provide a concentration of10 mg/mL.

    ______________________________________                                        Ingredients          Amount                                                   ______________________________________                                        Ivermectin           1.0%     w/v                                             Glycerol Formal      40.0%    v/v                                             Propylene Glycol q.s.                                                                              100.00%  v/v                                             ______________________________________                                    

Dissolve the ivermectin in either the glycerol formal, the propyleneglycol or a mixture of the solvents. When the dissolution is complete,adjust the volume to the final desired volume. Sterilize the finalsolution by membrane filtration and package it aseptically, providing 10mg of ivermectin per mL of solution.

EXAMPLE 2 Ivermectin Injectable Solution

A sterile solution suitable for rectal or subcutaneous administration isprepared using the following formulation to provide a concentration of10mg/mL.

    ______________________________________                                        Ingredients          Amount                                                   ______________________________________                                        Ivermectin           1.0%     w/v                                             Water for Injection  10.0%    v/v                                             Propylene Glyool q.s.                                                                              100.00%  v/v                                             ______________________________________                                    

Dissolve the ivermectin in a part of the propylene glycol. Add the waterfor injection so the precipitation of ivermectin is avoided and adjustthe volume with the remaining propylene glycol to the desired finalconcentration. Sterilize the solution by membrane filtration and packageit aseptically.

EXAMPLE 3 Treatment of Seizure Disorders

Eleven patients ages 7 to 79 years were treated with the ivermectincomposition prepared in Example 1. The doses ranged from 0.2 mg/kg to1.3 mg/kg. The methods of administration were either by subcutaneousinjection or rectal administration. The ivermectin was administered atintervals of from 3 days to 7 days. Patients Nos. 1-10 were afflictedwith epilepsy, manifesting as either absence, focal, or generalized(tonic-clonic) or gran mal seizures. Five patients had concomitantmental retardation and five were of normal intellectual status. Onepatient, No. 11, had Alzheimer's disease of approximately 4 years'duration, with essentially complete loss of short-term memory. She hadevolved to the stage of mild-moderate paranoid ideation and occasionalaggressive, combative conduct prior to ivermectin administration.

The following table shows the results.

                                      TABLE 1                                     __________________________________________________________________________    Treatment of Normal or Mentally Deficient Patients                            with or without Seizure Disorders                                                            Dosage                                                         Patient                                                                           Type of    Amount                                                                             Dosage                                                                              Mode of Results                                     No. Seizure    (mg/kg)                                                                            Frequency                                                                           Administration                                                                        Observed                                    __________________________________________________________________________    1.* generalized                                                                              0.2-0.4                                                                            q 5-6 days                                                                          subcutaneous                                                                          seizures controlled**,                          (nocturnal)           or rectal                                                                             no spasticity,                                                                increased attention span,                                                     increased responsiveness and emotions       2.* gran mal   0.4-0.6                                                                            q 6-7 days                                                                          subcutaneous                                                                          seizures controlled**,                                                or rectal                                                                             not aggressive and combative,                                                 sleeps well, happy, shows emotions          3.* none (spastic                                                                            0.6  q 5-6 days                                                                          subcutaneous                                                                          much less spasms,                               quadriparesis)        or rectal                                                                             happy, non-combative, sleeps well,                                            more interest in surroundings and                                             initiation, improved mobility               4.* gran mal and                                                                             0.7-1.3                                                                            q 5-6 days                                                                          subcutaneous                                                                          seizures controlled**                           absence (very         or rectal                                                                             better sleep, less agitated,                    frequent)                     increased attention span                    5.* focal (Jacksonian)                                                                       0.4-0.7                                                                            q 3 days                                                                            subcutaneous                                                                          seizures controlled**                           (continuous)          or rectal                                                                             sleeps well, now speaks                     6.  generalized                                                                              0.2  weekly                                                                              subcutaneous                                                                          seizures controlled**,                                                        sleeps well, less depression,                                                 increased emotional expression              7.  generalized                                                                              0.2-0.3                                                                            weekly                                                                              subcutaneous                                                                          seizures oontrolled**,                          and absence                   less depression, sleeps well,                                                 better mood, stopped snoring                8.  generalized                                                                              0.2-0.4                                                                            weekly                                                                              subcutaneous                                                                          seizures controlled**,                          and absence                   sleeps well, less depressed,                                                  increased emotional expression,                                               stopped snoring                             9.  generalized                                                                              0.2-0.4                                                                            weekly                                                                              subcutaneous                                                                          seizures controlled**,                          and focal (Jacksonian)        less depressed, better mood,                                                  better stress tolerance                     10. generalized                                                                              0.2-0.3                                                                            weekly                                                                              subcutaneous                                                                          seizures controlled**                                                         sleeps well, less depressed,                                                  no abusive and violent behavior             11. none       0.2  weekly                                                                              subcutaneous                                                                          marked improvement of behavior                  (Alzheimer's disease)                                                     __________________________________________________________________________     *Mentally retarded                                                            **Decreased or no dose of other antiepileptic drugs needed after              ivermectin                                                               

As can be seen from the results in Table 1, a considerable degree ofseizure control was obtained in all epileptic patients. Administrationtwo times a week was required in some cases. The intellectually normalpatients reported improved sleep-wake cycles, resolution ofconstipation, less angry behavior, less depression, and a markedlybetter mood. Two patients with partial sleep apnea (Nos. 7 and 8) havestopped snoring at night. The most striking changes have occurred in thepatients with seizures and concomitant metal retardation. Aggressive,violent behavior had virtually ceased, and the patients are much moreattentive to and affectionate toward the caretaker. Where therepreviously was apathy and disinterest in the environment, there is now amarked interest in the surroundings and the patients now appear to becapable of pleasure. They have also begun to utter sounds and to attemptto ambulate and to assist in self-feeding and dressing. Severeconstipation has resolved, and bladder control is much improved. Duringthe day, the patients signaled the need to urinate and at nightbedwetting either stopped or diminished. The patient with Alzheimer'sdisease has shown marked improvement in her conduct, although memory andorientation remain impaired.

EXAMPLE 4 Treatment of Movement Disorders

Three patients with Huntington's chorea, two patients with generalized(familial) tremor, one patient with muscular dystonia and spasticretrocollis, and two patients with congenital degeneration, of the basalganglia, one patient with dystonia musculorum deformans, and onepatient, with Parkinson's disease were treated with the ivermectincomposition prepared in Example 1. The doses ranged from 0.2 mg/kg to1.0 mg/kg. The methods of administration were either by subcutaneousinjection or rectal administration. The ivermectin was administered atintervals of from 7 days to 4 months.

The following table shows the results.

                                      TABLE 2                                     __________________________________________________________________________    Treatment of Movement Disorders                                                           Dose                                                              Patient     Amount                                                                             Dose  Route of                                                                              Results                                        No. Disease (mg/kg)                                                                            Frequency                                                                           Administration                                                                        Observed                                       __________________________________________________________________________    1.  Huntington's                                                                          0.4  weekly and                                                                          subcutaneous                                                                          much less intense dystonia,                        chorea       q month                                                                             or rectal                                                                             sleeps well, less depressed,                                                  better mood,                                                                  more emotionally responsive                    2.  Huntington's                                                                          0.3-0.8                                                                            weekly and                                                                          subcutaneous                                                                          40-50% decrease in dystonia,                       chorea       q 1-2 weeks                                                                         or rectal                                                                             less depressed, sleeps well,                                                  better mood,                                                                  more emotionally responsive                    3.  Huntington's                                                                          0.3-0.6                                                                            weeky and                                                                           subcutaneous                                                                          much less intense dystonia,                        chorea       q month                                                                             or rectal                                                                             less depressed,                                                               stopped smoking and drinking,                                                 no abusive behavior                            4.  generalized                                                                           0.3-0.4                                                                            weekly and                                                                          subcutaneous                                                                          90% decrease in tremor                             tremor       q 2 months    sleeps well, speech improved                       (familial)                                                                5.  generalized                                                                           0.2-0.4                                                                            weekly and                                                                          subcutaneous                                                                          90% decrease in tremor                             tremor       q 2 months    no dystonia, sleeps well,                          (familial)                 better mood,                                       (with dystonia)            not aggressive and angry                       6.  spastic 0.2  q 4 months                                                                          subcutaneous                                                                          retrocollis and                                    retrocollis                dystonia markedly decreased,                       (with dystonia)            sleeps well, better mood                       7.  dystonia                                                                              0.2-1.0                                                                            weekly                                                                              subcutaneous                                                                          leas dystonia,                                     musculorum         or rectal                                                                             markedly better                                    deformans                  body posture                                   8.  basal ganglia                                                                         0.4-0.6                                                                            q 5-10                                                                              subcutaneous                                                                          80% decrease in dystonia                           degeneration days  or rectal                                                                             and spasticity,                                    (familial)                 speech improved, walking improved              9.  basal ganglia                                                                         0.4  weekly                                                                              subcutaneous                                                                          much less dystonia                                 degeneration       or rectal                                                                             and spasticity,                                    (familial)                 speech improved,                                                              swallowing better                              10. Parkinson's                                                                           0.3  weekly                                                                              subcutaneous                                                                          100% decrease in rigidity                          disease            or rectal                                                                             variable decrease in tremor                    __________________________________________________________________________

As can be seen from the data in the table, the two patients withgeneralized (familial) tremor have experienced an estimated 90%reduction in the tremor. In addition, their sleep-wake cycles andfrequency of bowel movements have improved, their associated dystonicmovements have disappeared, their mood and enjoyment of life is farbetter, and they are much less depressed. In one of the two patients(patient No. 5), blood pressure after drug administration has remainedwell controlled despite discontinuation of her usual anti-hypertensivemedication. Before drug administration, another patient (patient No. 4)suffered from moderately severe congestive heart failure with 2-pilloworthopnea and frequent paroxysmal nocturnal dyspnea. These symptomsdisappeared after the first dose of drug and have not returned.

The data show that the patient with spastic retrocollis is estimated tohave 70%-90% less intense and frequent retrocollis spasms. He alsoreports no pain, less constipation, a regularized sleep-wake cycle, abetter mood, and less depression.

The data also show that the three patients with Huntington's chorea haveexperienced a marked diminution, estimated at 50-80%, of their dystonicmovements. In addition, they are no longer irritable, withdrawn anddepressed, enjoy life more, sleep better, and report no moreconstipation. One patient, (patient No. 3) who was frankly abusive tohis family and a heavy smoker and drinker, reports that his workperformance is better and that he no longer has a desire to smoke ordrink. His family reported that his angry mood and abusive behavior haveceased.

As the data show, the two patients with congenital degeneration of thebasal ganglia noted an estimated 80% decrease in both spasticity anddystonic movements. They also are no longer constipated, sleep well, andare no longer depressed. Their severe spastic dysarthria has improved,approximately 50% for patient No. 10 and approximately 80% in the caseof patient No. 9.

EXAMPLE 5 Treatment of Patients with Acquired Lesions of the CentralNervous System Associated with Spasticity

Four patients in this group were treated with the ivermectin compositionprepared in Example 1. The doses ranged from 0.1 mg/kg to 0.8 mg/kg. Themethods of administration were by subcutaneous injection. The ivermectinwas administered at weekly intervals. The following table shoves theresults.

                                      TABLE 3                                     __________________________________________________________________________    Treatment of Patients with Spasticity from Nervous-System Damage                              Dosage                                                        Patient         Amount                                                                             Dosage                                                                              Route of                                                                              Results                                    No. Disease     mg/kg                                                                              Frequency                                                                           Administration                                                                        Observed                                   __________________________________________________________________________    1.  left cerebrovascular                                                                      0.3  weekly                                                                              subcutaneous                                                                          decreased spasticity,                          accident (ischemic)            gait better,                                                                  marked improvement in speech fluency       2   meningoencephalitis                                                                       0.2-0.8                                                                            weekly                                                                              subcutaneous                                                                          markedly decreased spasticity,                                                gait better                                3.  left cerebrovascular                                                                      0.1-0.6                                                                            weekly                                                                              subcutaneous                                                                          less spasticity,                               accident (hemorrhagic)         gait better                                4.  left cerebrovascular                                                                      0.1-0.3                                                                            weekly                                                                              subcutaneous                                                                          less spasticity,                               accident (ischemic)            gait better,                                                                  improvement in speech                      __________________________________________________________________________                                       fluency                                

As is apparent from the data in Table 3, the spasticity of each of thepatients decreased, and all had increased fluidity of movement andimproved gait. The most striking change in the aphasic patients was morefluent and less dysarthic speech.

EXAMPLE 6 Treatment of Spasticity Caused by Spinal Cord Injury

Thirteen patients with spinal cord injury and concomitant spasticitywere treated with the ivermectin composition prepared in Example 1. Thedoses, which were administered in an ascending-dose fashion, ranged from0.2 mg/kg to 1.6 mg/kg. The method of administration were either bysubcutaneous injection or rectal administration. The etiologies includedtrauma from gun-shot wound (patients Nos. 2, 4, 10, 11, 12, and 13),blunt trauma (patients Nos. 1, 8, and 9), penetrating instrument wound(patient No. 3), arachnoiditis (patient No. 5), tropical spasticparaparesis (patient No. 6), and cervical myelopathy (patient No. 7).The ivermectin was administered at intervals of from 7 days to 3 months.The following table shows the results.

                                      TABLE 4                                     __________________________________________________________________________    Treatment of Spasticity Caused by Spinal Cord Injury                                         Dosage                                                         Patient                                                                           Nature     Amount                                                                             Dosage Route of                                                                              Results                                    No. of Injury  mg/kg                                                                              Frequency                                                                            Administration                                                                        Observed*                                  __________________________________________________________________________    1.  C8-T1 contusion;                                                                         0.2-1.2                                                                            biweekly and                                                                         subcutaneous                                                                          100% decreased spasms,                         Frankel Class A q 2-3 months   tone normal, stands with support,                                             moves feet, sensation unchanged            2.  T4 gunshot wound;                                                                        0.2-1.6                                                                            biweekly and                                                                         subcutaneous                                                                          80% decreased spasms,                          Frankel Class A q 2 months     tone normal, stands and crawls,                                               sensation to L4 level                      3.  C5 knife wound;                                                                          0.2-1.2                                                                            biweekly and                                                                         subcutaneous                                                                          100% decreased spasms,                         Frankel Class C                                                                          1.2  q 3 months     tone normal, better gait,                                                     better sensation                           4.  C5 gunshot wound;                                                                        0.2-0.8                                                                            biweekly and                                                                         subcutaneous                                                                          80-100% decreased spasms,                      Frankel Class C q 3 months     tone normal, stands,                                                          sensation to L5-S1 level                   5.  lumbar arachnoiditis;                                                                    0.2-1.2                                                                            biweekly and                                                                         subcutaneous                                                                          80-100% decreased spasms,                      Frankel Class D q week         tone normal, walks with walker,                                               better sensation                           6.  tropical spastic                                                                         0.2-1.0                                                                            biweekly                                                                             subcutaneous                                                                          100% decreased spasms,                         paraparesis;                   tone still high,                               Frankel Class D                better walking,                                                               sensation unchanged (normal)               7.  C5 cervical                                                                              0.2-0.4                                                                            biweekly and                                                                         subcutaneous                                                                          80-100% decreased spasms,                      myelopathy;     q week         tone normal walks with support,                Frankel Class C                sensation unchanged (normal)               8.  T6 fracture-                                                                             0.4-0.6                                                                            biweeky and                                                                          subcutaneous                                                                          80% decreased spasms,                          dislocation;    q week         tone normal, stands,                           Frankel Class A                sensation unchanged                        9.  C5-6 fracture-                                                                           0.45 weekly subcutaneous                                                                          80% decreased spasms,                          dislocation;                   tone normal,                                   Frankel Class B                no data on motor and sensory function      10. T5 gunshot wound;                                                                        0.2-1.2                                                                            biweekly and                                                                         subcutaneous                                                                          80-100% decreased spasms,                      Frankel Class A q week or rectal                                                                             tone normal, better trunk control,                                            sensation to L1 level                      11. C8 gunshot wound;                                                                        0.4-0.8                                                                            weekly subcutaneous                                                                          no data on motor and sensory function          Frankel Class B                                                           12. T1 gunshot wound;                                                                        0.3-0.6                                                                            weekly subcutaneous                                                                          decreased spasms,                              Frankel Class B                improved sensation                         13. C2 gunshot wound;                                                                        0.2  single subcutaneous                                                                          no changes noted                               Frankel Class B                                                                          dose                                                           __________________________________________________________________________     *Results only on spasms, tone, and motor plus sensory function. See text      for other observations.                                                  

The data show that as a result of the treatment, at least 10 of the 13patients showed a marked (80-100%) decrease in spasms. Concomitantly,was a reduction in muscle tone to normal levels.

In addition, in most cases, the anti-spasticity effects were transient,that is, they lasted 24-96 hours or were absent, at doses of 0.2-0.4mg/kg of body weight. More positive effects became apparent at doses of0.6-1.6 mg/kg. At the higher dosage range, spasms were essentiallycompletely abolished, and this effect persisted for intervals up tothree months after the last dose of ivermectin. There were clear dose-and time- response relationships as the doses increased in all thepatients who received successive doses, with progressively greaterdecreases in the severity of the spasms and longer periods of spasmdiminution or absence after, the administration of each dose. Othernoteworthy changes included improved mood and emotional status, lessdepression, improved sexual function, better bladder and bowel actionand regulation, moderate to marked improvement in the extent ofcutaneous sensation below the level of the lesion, i.e. from T4 to L4,or from C5 to S1, and a decrease in excessive Sympathetic nervous-systemactivity, i.e., less profuse sweating above the level of the lesion.

Using the composition of Example 1 and the dosage regimen of Example 6,the avermectins are expected to interact with G proteins (G proteinsbind to guanosine nucleotides), which are utilized in many Organs of thebody, including the nervous system, to transmit signals to the interiorof cells following the binding of molecules to receptors on the cellsurface. In addition to being involved with neurotransmitter release andaction, G proteins are also present in malignant cells, where theyappear to play a role in the creation and maintenance of the malignantstate, see Marx, Research News 1317, (Mar. 15, 1991). The G proteins mayalso be associated with the development of resistance tochemotherapeutic agents. See Grisslinger, et al., Lancet, 336, 1078,(1990). By blocking a G protein active site, the avermectins areexpected to successfully treat and palliate malignancies, as well as toreduce or eliminate development of resistance to chemotherapeuticagents. It is also expected the avermectins would facilitate there-establishment of normal and appropriate body homeostatic mechanismsvia their actions on the nervous system.

In addition it is expected that the avermectins will, because of theireffects on the nervous system, be useful to treat autoimmune diseases inwhich the nervous system plays a role, e.g. rheumatoid arthritis,osteoarthritis, systemic lupus erythematosus, spondyloarthropathies,Crohn's disease, ulcerative colitis, and other connective-tissuedisorders. See Levine, et al., Science, 226, 547-549, (1984), Thompson,et al., Ann. Rheum.Dis. 21, 370-377, (1962), and Bland, et al.,Arthritis and Rheum., 11 72-79, (1968).

We claim:
 1. A method for treating or controlling behavior problemscaused by diseases of human nervous system dysregulation and/ordysfunction, which comprises administering to a patient in need of suchtreating or controlling an effective amount of a compound of theavermectin family.
 2. A method of claim 1 wherein the avermectincompound administered is ivermectin.
 3. A method of claim 1 wherein theavermectin compound is administered at doses up to 1.6 mg/kg atintervals of from 3 days to 4 months.
 4. A method of claim 1 wherein thebehavior problems treated or controller are caused by major affectivedisorders, addictive, borderline, or disordered personality states,depression, congenital or acquired brain injury, and Alzheimer'sdisease.
 5. A method of claim 1 wherein the method of administration isrectal.
 6. A method of claim 1 wherein the method of administration issubcutaneous injection.
 7. A method of claim 1 wherein the method ofadministration is oral.
 8. A method of claim 1 wherein the method ofadministration is transdermal.